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Research Paper|Volume 12, Issue 2|pp 1272—1284

FOXO4-DRI alleviates age-related testosterone secretion insufficiency by targeting senescent Leydig cells in aged mice

Chi Zhang1,2, Yun Xie1,3, Haicheng Chen1, Linyan Lv2,4, Jiahui Yao1, Min Zhang1, Kai Xia1, Xin Feng1, Yanqing Li2, Xiaoyan Liang2, Xiangzhou Sun1, Chunhua Deng1, Guihua Liu2
  • 1Department of Andrology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
  • 2Reproductive Medicine Research Center, The Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, China
  • 3Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou 510000, China
  • 4Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, Guangzhou 510000, China
* Equal contribution
Received: October 7, 2019Accepted: December 25, 2019Published: January 20, 2020
https://doi.org/10.18632/aging.102682

Copyright: © 2020 Zhang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Male late-onset hypogonadism is an age-related disease, the core mechanism of which is dysfunction of senescent Leydig cells. Recent studies have shown that elimination of senescent cells can restore proper homeostasis to aging tissue. In the present study, we found that the fork head box O (FOXO) transcription factor FOXO4 was specially expressed in human Leydig cells and that its translocation to the nucleus in the elderly was related to decreased testosterone synthesis. Using hydrogen peroxide-induced senescent TM3 Leydig cells as an in vitro model, we observed that FOXO4 maintains the viability of senescent Leydig cells and suppresses their apoptosis. By disrupting the FOXO4-p53 interaction, FOXO4-DRI, a specific FOXO4 blocker, selectively induced p53 nuclear exclusion and apoptosis in senescent Leydig cells. In naturally aged mice, FOXO4-DRI improved the testicular microenvironment and alleviated age-related testosterone secretion insufficiency. These findings reveal the therapeutic potential of FOXO4-DRI for the treatment of male late-onset hypogonadism.